The present invention is concerned with a novel process for the manufacture of d,1-.alpha.-tocopherol by the catalyzed condensation of trimethylhydroquinone with isophytol. As is known, d,1-.alpha.-tocopherol is a diastereomer mixture of 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-tridecyl)-6-chromanol (.alpha.-tocopherol), which is the most active and industrially most important member of the vitamin E group.
Various processes for the manufacture of d,1-.alpha.-tocopherol by the condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) in the presence of a catalyst or catalyst system have already been described. These processes go back to the work of Karrer et al., Bergel et al. as well as Smith et al. see Helv. Chim. Acta 21, 520 et seq. (1938), Nature 142, 36 et seq. (1938) and, respectively, Science 88, 37 et seq. (1938) and J. Am. Chem. Soc. 61, 2615 et seq. (1939)!. While Karrer et al. carried out the synthesis of d,1-.alpha.-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (a Lewis acid), not only Bergel et al. but also Smith et al. used TMHQ and phytol as starting materials. In the following years mainly modifications, e.g. alternative solvents and Lewis acids, were developed. From the work of Karrer et al. there was developed in the year 1941 a technically interesting process for the manufacture of d,1-.alpha.-tocopherol, which was based on the condensation of TMHQ with IP in the presence of the catalyst system zinc chloride/hydrochloric acid (U.S. Pat. No. 2,411,969). Later publications, e.g. Japanese Patent Publications (Kokai) 54380/1985, 64977/1985 and 226979/1987 see Chemical Abstracts (C.A.) 103, 123731s (1985), C.A. 103, 104799d (1985) and, respectively, C.A. 110, 39217r (1989)!, describe this condensation in the presence of zinc and zinc chloride (ZnCl.sub.2) and a protonic acid, such as a hydrohalic acid, e.g. hydrochloric acid (HCl), trichloroacetic acid, acetic acid and the like, especially ZnCl.sub.2 /HCl, as the catalyst system.
The manufacture of d,1-.alpha.-tocopherol by the reaction of TMHQ with phytyl chloride or isophytol in the presence of boron trifluoride (BF.sub.3) or its etherate (BF.sub.3 Et.sub.2 O) is described in German Offenlegungsschriften (DOS) 960720 and 1015446 as well as in U.S. Pat. Nos. 3,444,123 and 4,634,781. However, boron trifluoride has corrosive properties.
Also, the condensation of TMHQ with IP or phytol, which has been treated with ammonia or amines, in the presence of ZnCl.sub.2 /HCl or a Lewis acid, e.g. BF.sub.3 or aluminium trichloride (AlCl.sub.3), and hydrochloric acid as the catalyst system has been described in the patent literature, e.g. in DOS 2 606 830, U.S. Pat. No. 4,634,781 and European Patent Publication (EP) 100471. Again corrosion problems occur.
A further interesting method for the manufacture of d,1-.alpha.-tocopherol from TMHQ and IP comprises using isolated TMHQ-AlCl.sub.3 complexes (DOS 1909164). This process variant avoids to a large extent the formation of undesired byproducts because it involves mild reaction conditions. The yield of d,1-.alpha.-tocopherol is given as 77% based on IP. The use of solvent mixtures, such as e.g. methylene chloride/nitromethane, is disadvantageous.
Using the reaction described in the literature of TMHQ with IP in the presence of ZnCl.sub.2 in combination with acids such as trichloroacetic acid, acetic acid or acidic salts, such as sodium hydrogen sulphate, d,1-.alpha.-tocopherol cannot be manufactured in the required purity (about 85%) (see, for example, DOS 1909164).
A further application of ZnCl.sub.2 - with the addition of bromine--in the condensation of TMHQ with IP is disclosed in Czechoslovakian Patent 205952.
A further method for the condensation of TMHQ with IP to d,1-.alpha.-tocopherol is effected using a mixture of silicic acid and aluminium oxide pre-treated with protonic acids (see DOS 2404621). This method gives d,1-.alpha.-tocopherol in 90% yield; the required excess of IP (based on TMHQ) is, however, disadvantageous.
The manufacture of d,1-.alpha.-tocopherol by the condensation of TMHQ with IP using ion exchangers in combination with metal ions (Zn.sup.2+, Sn.sup.2+ and Sn.sup.4+) disclosed in Bull Chem, Soc. Japan 50, 2477 et seq. (1977) gives the product in 70-87.5% yield.
All processes using ZnCl.sub.2 in combination with Bronsted acids as catalyst systems feature as a disadvantage the occurrence of corrosion problems and a potential contamination of the waste water with zinc ions.
The use of ion exchangers (Amberlyst.RTM. 15) as the catalyst for the condensation of TMHQ with IP is described in U.S. Pat. No. 3,459,773. However, the d,1-.alpha.-tocopherol could not be obtained in the requisite purity.
The manufacture of d,1-.alpha.-tocopherol in liquid or super-critical carbon dioxide by the condensation of TMHQ with IP in the presence of ion exchangers takes place according to EP 603 695 in about 85% yield.
The condensation in the presence of a catalyst system which consists of iron(II) chloride, metallic iron and hydrogen chloride gas is described in DOS 2160103 and U.S. Pat. No. 3,789,086. The formation of less byproducts is advantageous compared with the aforementioned process using zinc chloride and hydrochloric acid. However, corrosion problems and chloride contamination are equally disadvantageous.
An interesting alternative for the condensation of TMHQ with IP to d,1-.alpha.-tocopherol comprises using trifluoroacetic acid (EP 12824). Of advantage in this process are the good recyclization of the acid and the avoidance of hydrochloric acid. Disadvantageous are the facts that trifluoroacetic acid is relatively expensive and suitable materials for a production process are difficult to obtain.
The use of heterogeneous silicate-based catalysts (clays; especially zeolites) for the condensation is described in C.A. 100, 22833 (1984) and gives d,1-.alpha.-tocopherol in a yield of about 92%.
The use of heteropolytungsten acids as catalysts for the condensation of TMHQ with IP has been described for the first time in React. Kinet. Catal. Lett. 47, 59 et seq. (1992). d, 1-.alpha.-Tocopherol could be obtained in 90% yield with this process using toluene as the solvent. The separation of the catalyst and more precise experimental details, such as e.g. the dosage of the isophytol, are, however, not described in this literature reference. The excess of IP based on TMHQ is a disadvantage.
A further process described in the literature for the synthesis of d,1-.alpha.-tocopherol is based on the use of lathanide triflates, such as e.g. scandium trifluoromethanesulphonate. With a 10% excess of IP this process gives yields of 96-98% EP 658 552; Bull. Chem. Soc. Japan 68, 3569 et seq. (1995)!.
The use of scandium chlorides and other chlorides (yttrium, lanthanum etc.) on a carrier, e.g. bentonite or montmorillonite, as the catalyst for the condensation of TMHQ with IP has as disadvantages the need for a large amount of catalyst and an excess (about 10%) of IP EP 677 522; Bull. Chem. Soc. Japan 69, 137 et seq. (1996)!.
According to EP 694 544 the condensation of TMHQ with IP in isopropyl acetate catalyzed by ZnCl.sub.2 /HCl gives d,1-.alpha.-tocopherol in yields of 98.6% with a purity of 98.6%. Disadvantageous in this process are, in addition to the contamination of the waste water by zinc ions, the large "catalyst amounts" (e.g. 23.3 g of ZnCl.sub.2 for 67 g of product) and the isophytol excess.
From the forgoing explanations it will be evident that the previously known processes have considerable disadvantages. Thus, corrosion problems occur in the case of all processes, when boron trifluoride is used toxicity problems with the boron trifluoride adducts also occur and when iron or zinc is used there is a contamination of the waste water with iron or zinc ions which is today no longer acceptable. In the case of some processes the formation of undesired byproducts, e.g. phytyltoluene and chlorophytols, is an especially serious problem.